There are approximately 100 millions people in the world that are diabetic, and many millions of them are in the U.S. Knowledge of blood glucose composition is of crucial importance for treating diabetes. Moreover, information on variations of blood glucose level during an extended period of time is very important in a diabetic patient's daily life since poor glucose control over time can lead to severe complications, including blindness, kidney failure, heart failure, limb pain, poor circulation and subsequent amputation. Currently, diabetic patients must use often painful and cumbersome tests requiring them to repeatedly lance their finger and draw blood. After separate setup steps, including drawing blood with a lancet, the blood is then placed on a diagnostic test strip composed of chemicals sensitive the glucose in the blood sample, and the strip is read by a meter. In order to properly monitor and control the glucose level, an adult diabetic must normally take blood measurements 4-7 times a day, while children and elderly etc. may need to take blood samples up to 10 times daily. The tests are painful and costly, and the blood disposal and contamination are also potential problems.
For a number of years, attempts have been made to determine blood glucose level non-invasively (or in vivo) using optical radiation, or in general, lightwave technologies. For example, techniques including visible, near-infrared (IR) spectroscopy, mid-infrared (MIR) spectroscopy, infrared (IR) spectroscopy, polarization changes, scatter changes, photoacoustic spectroscopy, Raman scattering through tissue or human eyes, etc. To date, none of these approaches have been feasible, furthermore, none of the other types of non-invasive technology has been feasible either. As a result, there is a need for a personal or clinical non-invasive glucose monitoring system for monitoring blood glucose level without pain and requiring the drawing of a blood sample.
Visible and near-infrared (NR) spectroscopic techniques have been used to measure blood glucose level non-invasively. These techniques utilize optical radiation in the wavelength range of 600 nm-2500 nm, to measure basically the absorption of glucose in blood by either transmitting the optical radiation through, or reflecting from, a portion of human tissue, such as a finger or ear lobe. The absorption spectra obtained from the measurements are then analyzed to derive the glucose level. These techniques cannot satisfy the need to monitor glucose level non-invasively due to the many intrinsic drawbacks of NIR spectroscopy. It is known that NR wavelengths do not measure fundamental vibrational transition modes of molecules; only longer wavelengths, i.e., mid-infrared (MIR) and infrared (IR) wavelengths can measure the fundamental vibrational transitions which produce spectral "finger-print" effects. For example, IR spectroscopic techniques generate specific, sharp spectral peaks that directly correlate to specific molecules, and the height of the spectral peaks are directly proportional to the concentration of the molecules. However, NIR spectra contain many harmonics of overtones as well as a combination of various fundamental vibration transitions. There is small possibility of a specific spectral peak that directly correlates to a specific molecule, i.e., the enegetics associated with overtones and combination of absorption results in absorption bands that are broad and featureless with low absorptivities. Moreover, glucose produces one of the weakest NIR absorption signals per concentration unit of the body's major components. For example, water has very strong absorption signals in the NIR region, especially in the 900-2500 nm wavelength regions. Since a large portion of human tissue is water, it is very difficult, if not impossible, to make non-invasive glucose measurement using NIR techniques without water interference. Furthermore, NIR techniques are vulnerable to interference from environmental variations, such as temperature, humidity changes; thus, it is hardly acceptable for home or clinical use. Despite the fact that many attempt have been made over the years, NIR techniques are still unable to measure blood glucose non-invasively. Due to the many aforementioned drawbacks of the NIR techniques, none of the devices based on the techniques have been able to measure the blood glucose level accurately and repeatedly.
In other prior art technologies, mid-infrared (MIR) and Infrared (IR) techniques are used in a similar fashion as the aforementioned NIR techniques. For example, these techniques utilize optical radiation in the wavelength range of 3000 nm-10,000 nm to measure basically the absorption of glucose in blood in a portion of human tissue, such as a finger or ear lobe or even a lip. These technologies in principle correct the major drawbacks that are associated with NIR technology, in that the MIR techniques generate spectra containing fundamental vibrational transitions. The water interference to these longer wavelengths, however, is orders of magnitude stronger than that of the NIR region. It is evident in many publications and acknowledged in prior art that the absorption of human skin is substantially higher for longer wavelengths, and absorption is nonlinear. For example, the strong absorption of human tissue is acknowledged in U.S. Pat. No. 5,553,616. Due to the strong interference from absorption of the skin (which is mainly water), MIR or IR optical radiation has a hard time penetrating to a reasonable depth of human tissue, thereby rendering infrared spectroscopic measurement useless in term of non-invasively monitoring blood glucose level.
In still another prior art technology, laser Raman spectroscopy is used to obtain glucose to concentration. In this process, a laser beam is focused into a human subject's eye where it interacts with the ocular aqueous humor and generates Raman scattering, which is collected and analyzed by a Raman spectrometer to obtain a Raman spectrum of the aqueous humor. The prior art claims that glucose concentration in the ocular aqueous humor can be derived from the Raman spectrum, then the blood glucose level can be inferred. Such process is described in U.S. Pat. No. 5,243,983. This technology in theory corrects some of the major drawbacks associated with the aforementioned NIR, MIR and IR technologies. For example, Raman spectroscopic techniques not only generate spectra with spectrally differentiable features for different constituents in a sample, but also employ visible (400-700 nm) and short NIR (800-1100 nm) wavelengths which are not absorbed by water as strongly as is the case with MIR and IR wavelengths. Despite of the fact that the device in the aforementioned U.S. Pat. No. 5,243,983 uses an optically more "clear window", i.e., the human eye, rather than human tissue, it is not an ideal device, and it may not even be a safe device. It is a known fact that the human eyes are very vulnerable to bright light illumination, especially laser radiation. The permissible level of laser exposure to the human eye is so low that it may not even be enough to produce the Raman signal required to derive the glucose concentration. Furthermore, eye safety is a major concern for such a device designed for daily home or clinic use by an average diabetic patient.
Raman spectroscopy is also used in other prior art devices to measure glucose non-invasively by focusing or delivering laser radiation directly to human tissues to measure concentrations of blood glucose or other analytes such as blood gases in vivo. The laser beam interacts with a portion of human skin or an index finger and generates Raman scattering, which is collected and analyzed by a Raman spectrometer to obtain a Raman spectrum. Despite the fact that these prior art methods using a laser to directly interact with human tissues and thus avoid the dangerous problems of laser safety associated with focusing a laser into the human eye, they still have major drawbacks and are thus still not successful.
The major drawback of the above-described prior art is the difficulty that the very weak Raman signal has in migrating through human tissue, which is mostly inhomogeneous turbid media. It is well known, as discussed in many publications, that Raman spectroscopy is based on inelastic light scattering in which scattered photons exchange energy with the sample. Raman scattering is a weak effect with only about 1 photon in 10.sup.6 -10.sup.8 incident on the sample exhibiting a Raman shift. One way to obtain more Raman signal is, to simply increase the excitation laser power to a higher level. This increasing of laser power, however, runs the risk of burning, or even vaporizing the turbid tissue. Furthermore, blood glucose concentration is low compared to many analytes in the human tissue, hence glucose also has very weak Raman signals compared to those of many other analytes, so the signal-to-noise ratio for glucose in tissue measurement is very small. Another drawback is that under laser illumination, human tissues' fluorescence signals are also very strong and tend to mask the already weak Raman signal. The drawbacks make Raman signals directly collected from turbid tissues useless for extracting glucose concentration. One of the Raman prior art references acknowledges the draw backs and attempts to use complicated mathematical methods, such as the so called "fuzzy adaptive resonance theory-mapping", (see U.S. Pat. No. 5,553,616), to extract glucose information from Raman tissue spectra obtained by direct laser illumination. Due to the intrinsic weakness of the signal-to-noise ratio of this type of tissue Raman spectra collection scheme, the method is not feasible for any practical use. Another Raman prior art reference acknowledges this drawback and uses a so called "compound parabolic concentrator", as detailed in U.S. Pat. No. 5,615,673, to enhance the collection efficiency of Raman signals produced from laser irradiation of human tissue. However, this method only increases the collection efficiency of any Raman signals generated from the tissue, and does not necessarily increase the Raman signal of blood glucose fundamentally. Again, due to the intrinsic weakness of the signal-to-noise ratio of this type of tissue Raman spectra collection scheme, the method is not feasible for any practical use.
The state-of-the-art non-invasive methods for measuring glucose non-invasively are not suitable for home and or clinical diabetic blood glucose applications. As a matter of fact, there is no non-invasive device available so far due to the aforementioned major drawbacks. Therefore, there is a need for a new non-invasive technology to overcome the problems associated with measuring blood glucose level in vivo in humans and other animal beings.